Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition

Abstract

The described invention provides compositions and methods for reducing progression of a fibrosis in a tissue of a subject selected from liver, kidney or vascular fibrosis, the progression of the fibrosis being characterized by aberrant fibroblast proliferation and extracellular matrix deposition in the tissue. The method includes administering a therapeutic amount of a pharmaceutical composition containing a polypeptide having the amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or functional equivalent thereof, and a pharmaceutically acceptable carrier, wherein the therapeutic amount of the polypeptide is effective to reduce progression of the fibrosis, to treat remodeling of the tissue, or a combination thereof.

What is claimed is: 
     
       1. A method for reducing progression of a fibrosis in liver tissue, kidney tissue or vascular tissue; treating fibrotic remodeling of the liver tissue, kidney tissue or vascular tissue; or both, in a subject in need thereof, comprising:
 administering to the subject a pharmaceutical composition comprising a therapeutic amount of a polypeptide of the amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof selected from the group consisting of a polypeptide of the amino acid sequence FAKLAARLYRKALARQLGVAA (SEQ ID NO: 3) and a polypeptide of the amino acid sequence KAFAKLAARLYRKALARQLGVAA (SEQ ID NO: 4), and a pharmaceutically acceptable carrier thereof, 
 progression of the fibrosis being characterized by one or more of aberrant fibroblast proliferation and extracellular matrix deposition producing remodeling in liver tissue, kidney tissue or vascular tissue, wherein the therapeutic amount of the pharmaceutical composition inhibits at least 65% of activity of MK2, MK3, CaMKI, and TrkB, with limited off-target kinase inhibition, and 
 wherein the therapeutic amount of the polypeptide reduces progression of the fibrosis, treats remodeling of the liver tissue, kidney tissue or vascular tissue due to the fibrosis, or both reduces progression of the fibrosis in liver, kidney or vascular tissue and treats remodeling of the liver tissue, kidney tissue or vascular tissue due to the fibrosis. 
 
     
     
       2. The method according to  claim 1 , wherein the tissue fibrosis is further characterized by an inflammation in the tissue. 
     
     
       3. The method according to  claim 2 , wherein the inflammation is an acute or a chronic inflammation. 
     
     
       4. The method according to  claim 2 , wherein the inflammation is mediated by at least one cytokine selected from the group consisting of Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and Interleukin-10 (IL-1β). 
     
     
       5. The method according to  claim 1 , wherein the aberrant fibroblast proliferation and extracellular matrix deposition in the tissue is characterized by an aberrant activity of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) in the tissue compared to the activity of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) in the tissue of a normal healthy control subject. 
     
     
       6. The method according to  claim 1 , wherein the step of administering occurs orally, intratracheally, parenterally, intravenously, or intraperitoneally. 
     
     
       7. The method according to  claim 1 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent. 
     
     
       8. The method according to  claim 7 , wherein the additional therapeutic agent is an anti-infective agent. 
     
     
       9. The method according to  claim 8 , wherein the anti-infective agent is an antiviral agent. 
     
     
       10. The method according to  claim 9 , wherein the antiviral agent is one or more of sofosbuvir, an HCV boosted protease inhibitor, a nonnucleoside NSSB inhibitor, an NS5a inhibitor, ABT-450 with ritonavir, ABT-450 co-formulated with ABT-267, ABT-450 formulated with sofosbuvir, and ribavirin. 
     
     
       11. The method according to  claim 7 , wherein the additional therapeutic agent is a glucocorticoid selected from the group consisting of prednisone, budesonide, mometasone furoate, fluticasone propionate, fluticasone furoate, and a combination thereof. 
     
     
       12. The method according to  claim 7 , wherein the additional therapeutic agent is an analgesic agent. 
     
     
       13. The method according to  claim 7 , wherein the additional therapeutic agent is selected from the group consisting of a purified bovine Type V collagen, an IL-13 receptor antagonist, a protein tyrosine kinase inhibitor, an endothelial receptor antagonist, a dual endothelin receptor antagonist, a prostacyclin analog, an anti-CTGF monoclonal antibody, an endothelin receptor antagonist, AB0024, a lysyl oxidase-like 2 (LOXL2) antibody, a c-Jun N-terminal kinase (JNK) inhibitor, pirfenidone, IFN-γ1b, a human antibody against all three TGF-β isoforms, a TGF-β activation inhibitor, a recombinant human Pentraxin-2 protein (rhPTX-2), a bispecific IL-4/IL-13 antibody, an antibody targeting integrin αvβ6, N-acetylcysteine, sildenafil, a Tumor Necrosis Factor (TNF) antagonist, and a combination thereof. 
     
     
       14. The method according to  claim 1 , wherein the carrier is selected from the group consisting of a controlled release carrier, a delayed release carrier, a sustained release carrier, and a long-term release carrier. 
     
     
       15. The method according to  claim 13 , wherein the endothelin receptor antagonist is A-selective. 
     
     
       16. The method according to  claim 13 , wherein the TNF antagonist is etanercept.